This project focuses on the characterization and exploitation of a focal seizure model developed in this laboratory. The preliminary results show for the first time that sustained electrical stimulation of a single excitatory pathway to the hippocampus of the rat replicates the precise pattern of hippocampal damage seen in the brains of chronic human epileptics. This selective pattern of hippocampal damage occurs without using convulsant chemicals, without causing motor convulsions, without interrupting respiration and without producing general hippocampal anoxia. It is the contention of the applicant that this focal seizure model represents a new and useful approach to the study of the epileptic state that will at least partially clarify the mechanism of seizure-associated brain damage as well as serve in the future to discover new, more selective drugs useful in the treatment of human seizure disorders. The proposed studies are designed: 1) to develop and characterize this focal seizure model. This will involve a detailed study of the functional and structural changes induced in the brain in the post-stimulation period. These experiments will utilize electrophysiological and light- and electron microscopic techniques. A main focus of the study will be to evaluate the effect of stimulation-induced seizure activity on inhibitory neurons and determine if ultrastructural and immunocytochemical correlates of decreased inhibition are evident; 2) to examine the role of a number of peptides in the epileptic state using immunocytochemical methods. The preliminary results show that the hippocampal interneurons most sensitive to the effects of seizure activity are the interneurons that contain cholecystokinin, vaso-active intestinal polypeptide or somatostatin. Therefore, the possible role of a loss of these peptides in the etiology or progression of the epileptic state will be examined; 3) to elucidate the mechanism of excitation-induced neuronal damage. This will involve electrophysiological and neuroanatomical experiments designed to determine if seizure-associated neuronal death requires excessive activation of neurons by potentially neurotoxic excitatory neurotransmitter or if cell death results from excitation per se, regardless of the means by which it is initiated.